It is well established that calorie restriction (3O-4O percent) prolongs the life span in rodents. Increased life span is accompanied by preventing the increase in body weight, maintaining cell-mediated immune function, and decreasing the incidence of malignancies and renal diseases. Although recent studies have revealed that CR alters the expression of various genes, particularly those involved in macromolecular damage, it remains unknown whether animals fed a lifelong CR diet are able to successfully ward off bacterial infection. Our recent studies showed that CR-fed young C57BL/6 mice are more susceptible to bacterial infection than AL-fed mice. The differences in susceptibility to infection could be due to differences in strains of mice, energy uptake, supplementation of vitamins and minerals or delayed maturity of humoral immunity. We, therefore, propose to compare 3 different commonly used diets for CR studies in 2 strains of mice (C57LBL/6 and Balb/C) which differ in their response to Th-1 and Th-2 cytokine expression. We will compare 1) the AIN-93 diet with and without additional vitamin supplements, 2) the AIN-93 CR diet with reduced carbohydrates but increased protein, fat and vitamins to equal the AL diet, and 3) NIH-3 1, an undefined but commonly used rodent chow diet for CR studies. We will measure the mortality rate from polymicrobial sepsis induced by cecal ligation and puncture (CLP) and from salmonellosis in young and old mice. To establish the susceptibility and resistance to infection both in young (8 mo) and old (24 mo) mice, we will carry out detailed functional studies of macrophages, Th-1 and Th-2 cytokine production, and cDNA superarray analysis for Th-1/Th-2 and inflammatory response cytokine genes. These studies will establish the role of CR in developing optimal immune function to ward off infection arising from common bacterial pathogens during aging. This new information may become very useful to prevent any sudden onset of infection during CR studies and/or studies of weight reduction either by diet or by drugs in humans.